NO154427B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 3-SUBSTITUTED HEXAHYDRO-PYRIMIDO (1,2-A) AZEPINES. - Google Patents

Description

The present invention relates to an analogue process for the production of therapeutically active, substituted hexahydropyrimido[1,2-a]azepines, their acid addition salts and quaternary salts.

In the literature, only certain 3-substituted pyrimido[1,2-a]azepines are described. 3-carbamoyl-4-oxo-4,6,7,8-hexahydro-pyrimido[1,2-a]azepine is obtained from 3-carbamoyl-4-imino-4,6,7,8,10-hexahydro-pyrimido [1,2-a]azepine as described in Aust. J. Chem. 2j8, 119 (1975). Ethyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine is obtained from 7-methoxy-3,4,5,6-tetrahydro-2H-azepine and diethyl -ethoxy-methylene-malonate in the presence of ammonium acetate. (Hungarian Patent Document No. 167,676 and Japanese Patent Document No. 7,334,897).

3-cyano-4-oxo-4,6,7,8,9,10-hexahydro-azepino-[1,2-a]pyrimidine is prepared in the presence of sodium ethylate from 7-amino-3,4,5,6- tetrahydro-2H-azepine and ethylethoxy-methylene-cyanoacetate (Hungarian patent document 167,676 and Japanese patent document 7,334,897). The present invention relates to an analogue method for the production of therapeutically active compounds of general formula

of a mixture of these and pharmaceutically suitable acid addition salts and quaternary salts, in which R denotes hydrogen or lower alkyl, R"'" denotes lower alkyl, phenyl, carboxyl, lower alkoxycarbonyl, nitrile, orabamovl, carbohydrazido, 2 ' 2 " 1 R b.denotes hydrogen, or R is lower alkyl only when -R is lower alkyl, provided that when R 2 in formula I b.denotes hydrogen, R"'" do not denote nitrile, alkoxycarbonyl or propyl in formula I. The analog method according to the invention is characterized in that a 7-amino-3,4,5,6-tetrahydro-2H-azepine derivative of general formula in which R is as indicated above, is reacted with an acrylic acid derivative of the general formula

in which R 2 is as stated above, R 3 denotes lower alkyl, phenyl, lower alkoxycarbonyl, nitrile, R 4 denotes hydrogen or lower alkyl, R 2 denotes lower alkyl, and if desired, that the resulting mixture ay 4-oxo -pyrimido[1,2-a]azepine of general formula I and 2-oxo-pyrimido[1,2-a]azepine of general formula II are separated from each other, and if desired a 2 1 compound obtained in which R and R are as stated above and R denotes alkoxycarbonyl,

a) is transferred by saponification in a carboxylic acid in which R and

2 1

R is as indicated above and R denotes carboxy, or

b) is transferred by reaction with ammonia to an acid amide in which R and R 2 are as indicated above and R 1 denotes

carbampyl, or

c) is transferred by reaction with hydrazine to a compound in which R and R <2> are as indicated above, and R represents

carbohydrazido,

and, if desired, that an obtained compound of general formula I or II is transferred to a pharmaceutically suitable acid addition salt or quaternary salt.

As compounds of general formula IV, dialkyl-ethoxy-methylene-malonate, alkyl-ethoxy-methylene-cyanoacetate, alkyl-2-formyl-propionate, alkyl-2-formyl-phenyl-acetate, ethyl-2-ethyl-acetoacetate are preferably used. As alkyl esters, methyl, ethyl, isopropyl, n-propyl esters are preferably considered.

The term "lower alkyl" stands for straight-chain or branched alkyl with 1-4 carbon atoms, such as, for example, ethyl, methyl, isopropyl, n-propyl, isobutyl, tert.-butyl.

The reaction between the compound of formula III and IV is preferably carried out in an inert solvent. Alcohols are preferably used as solvents, such as for example ethanol, methanol, esters for example ethyl acetate, ketones, e.g. acetone, ethyl methyl ketone, aromatic hydrocarbons, e.g. benzene, toluene etc. halogenated hydrocarbons, e.g. chloroform, carbon tetrachloride, chlorobenzene etc. as well as mixtures thereof.

The reaction can preferably be carried out at -15 - 150° C. According to a preferred embodiment of the method, a solution of the compound of general formula IV is added to a solution of the compounds of general formula III, but in some cases one can proceed in reverse order.

A mixture of the compounds of general formula I and II is obtained after removal of the solvent by distillation. The resulting mixture can, if desired, be separated due to different solubility, basicity or chromatographic conditions for the compounds of formula I and II.

The compounds of general formula I or

II in which R, R<1> and R<2> are as indicated above, can, if desired, be reacted with acids and acid addition salts or quaternary salts are obtained

salts by reaction with quaternization agents. The base

can be released from the salt and, if desired, the salt can be transferred to

other salts. Hydrochloride, hydrobromide, perchloric acid, acetic acid, salicylic acid salts as well as quaternary alkyl halides, e.g. methyl iodide, dialkyl sulfate, e.g. dimethyl sulfate, p-toluenesulfonate, benzenesulfonate.

The compounds of general formula IV are commercially available compounds, and the compounds of general formula III can be easily prepared from caprolactam optionally lower alkyl-substituted in the 7-position, the starting material being first reacted with an alkylating agent (e.g. diethyl sulfate) and the obtained O-alkyl iminoether is reacted with an ammonia-releasing agent, e.g. ammonium acetate, ammonium chloride, etc., forming a compound of general formula III.

The prepared compounds of general formula I or II exhibit excellent anti-anginal activity, which

is a new effect not previously known for this group of compounds, and the compounds can thus be used as pharmaceuticals.

When used in the pharmaceutical industry, the compounds of general formula I or II are mixed as active ingredients with inert non-toxic, solid or liquid diluents or carriers, and used in solid form, e.g. tablets, dragées, capsules, or in liquid form, e.g. solutions, suspensions or emulsions.

The following examples illustrate the invention.

Example 1

A solution of 67.2 g of 7-amino-3,4,5,6-tetrahydro-2H-a.zepine in 600 ml of ethanol was cooled to -10°C and a solution of 127.8 g of diethylethoxy-methylene-malonate in 600 ml of ethanol was added dropwise to the reaction mixture during 1 hour while stirring. The mixture was stirred for an additional 1 hour at -10 and -5°C and boiled for 1 hour. Ethanol was distilled from under reduced pressure. The remaining oil was distilled off under reduced pressure. The remaining yellow oil was a 10:1 mixture of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-[1,2-a]azepine-3-carboxylate and ethyl 2- oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate which was dissolved in 600 ml of benzene and extracted twice with 60 ml of water. The benzene solution was dried over anhydrous sodium sulfate and evaporated to reduced pressure. 114 g (80.5%) of ethyl 4-oxo-4,5,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate (known compound) were obtained.

The combined aqueous extract was extracted twice with 120 ml of chloroform, after which the combined solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure. 2.1 g (8.9%) of ethyl 2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate melting at 156 - 157°C.

Analysis: C-^H<->^g^<O>^

Calculated: C 61.00% H 6.82% N 11.85%

Found : C 60.91% H 6.87% N 11.81%

Example 2

A solution of 16 .9 g of ethyl-ethoxy-methylene-cyanoacetate in 120 ml of ethanol. The reaction mixture was stirred for 1 hour at room temperature and 1 hour under boiling. Ethanol was distilled off under reduced pressure. The remaining red oil was a 3:1 mixture of 3-cyano-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine and 3-cyano-2-oxo -2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine which was dissolved in 200 ml of benzene and extracted twice successively with a 5% w/v hydrochloric acid solution and with 10 ml of water. The benzene solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the residue was crystallized from ethanol. 4.6 g (24.2%) of 3-cyano-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine (known compound) were obtained.

The combined aqueous phases were neutralized with sodium bicarbonate and extracted with chloroform. The combined benzene solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the residue was crystallized from ethanol. 1.7 g (8.9%) of 3-cyano-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine melting at 205 - 205 °C.

Analysis: c OH 11 N 3 °

Calculated: C 63.51% H 5.86% N 22.22%

Found : C 63.9% H 5.90% N 21.97%

Example 3

To a solution of 11.2 g of 7-amino-3,4,5,6-tetra-hydro-2H-azepine in 100 ml of ethanol, 13.1 g of ethyl-2-formyl-propionate was added at room temperature and the reaction mixture was stirred for 24 hours and boiled for 3 hours. The ethanol was distilled off under reduced pressure, and the residue was treated with a mixture of acetone and petroleum ether. The precipitated crystals were filtered. 6.6 g (37%) of 3-methyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine were obtained which, after recrystallization from acetone, melts at 202 °C.

Analysis: C10<H1>4N20

Calculated: C 67.39% H 7.91% N 15.71%

Found : C 67.18% H 8.00% N 15.72%

The mother liquor containing acetone and petroleum ether was evaporated. The orange-red oil obtained was dissolved in 50 ml of benzene and treated with activated carbon and filtered, and saturated with anhydrous hydrogen chloride gas. The crystals obtained were filtered. 5.75 g (26.7%) of 3-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine hydrochloride melting at 207 °C.

Analysis: qE^5N20C1

Calculated: C 55.94% H 7.04% N 13.04% Cl 16.51%

Found: C 56.05% H 7.01% N 12.98% Cl 16.70% Example 4

11.8 g of ethyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-[1,2-a]azepine-3-carboxylate were dissolved in 40 ml of 30% by weight ammonium hydroxide solution , and the reaction mixture was allowed to stand for 2 hours at room temperature. The precipitated crystals were filtered and washed with water. 10.1 g (97.5%) of 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine melting at 234 - 235 were obtained °C.

Analysis: ciqH13<N>3°2

Calculated: C 57.96% H 6.32% N 20.27%

Found : C 57.88% H 6.30% N 20.34%

Example 5

The procedure was as described in example 4, but ethyl-2-oxo-2,6,7,8,9,10-hexa-hydro-pyrimido [1,2-a]azepine-3-carboxylate was used as starting material. 3-Carbaomyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine was obtained in a yield of 69% melting at 219°C.

Analysis: cio<H>13<N>3°2

Calculated: C 57.96% H 6.32% N 20.27%

Found : C 58.07% H 6.30% N 20.30%

Example 6

11.8 g of ethyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-11,2-a]azepine were dissolved in 50 ml of a 5% w/v sodium hydroxide solution , and allowed to stand for 2 hours at room temperature. The pH value of the solution was set to 3 by adding a 36% w/v hydrochloric acid solution. The precipitated crystals were filtered and washed with water. 9.25 g (91%) of 4-0x0-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylic acid were obtained which, after recrystallization from methanol, melts at 117 - 119° C during decomposition.

Analysis: c<qH>1<2N>2°3

Calculated: C 57.69% H 5.81% N 13.45%

Found : C 57.27% H 5.84% N 13.23%

Example 7

One proceeded as described in example 5 but used as starting material ethyl-2-oxo-2,6,7,8,9,10-hexa-hydro-pyrimido [1,2-a]azepine-3-carboxylate, and the 2-0x0-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylic acid was obtained in a yield of 67.4%, which melts at 198° C. with cleavage .

Analysis: iO<H>12<N2>°3

Calculated: C 57.69% H 5.81% N 13.45%

Found : C 57.31% H 5.88% N 13.21%

Example 8

2.36 g of ethyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-[1,2-a]azepine-3-carboxylate was obtained in 10 ml of 98% w/v hydrazine hydrate stand for 2 hours at room temperature, and the precipitated crystals were filtered, washed with water and ethanol. 1.8 g (81%) of 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-

[1,2-a]azepine-3-carbohydrazide melting at 184 - 186°C.

Analysis: C1Q<H>14<N>4<0>2

Calculated: C 54.04% H 6.35% N 25.21%

Found : C 53.93% H 6.41% N 25.48%

Example 9

One proceeded as described in example 8, but used as starting material ethyl-2-oxo-2,6,7,8,9,10-hexa-hydro-pyrimido [1,2-a]azepine-3-carboxylate and the was obtained 2-OxO-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carbohydrazide melting at 201° C. Yield: 74.30%.

Analysis: C^H^N^

Calculated: C 54.04% H 6.32% N 25.21%

Found : C 53.84% H 6.42% N 25.36%

Example 10

2.36 g of ethyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido-[1,2-a]azepine-3-carboxylate was allowed to stand in 5 ml of ethanol in the presence of 5 ml of methyl iodide for 72 hours at room temperature. The alcohol was removed by distillation. The remaining oil was treated with 20 ml of ethyl acetate. The ethyl acetate was decanted. The hygroscopic oil obtained was dried.

Analysis: C13Hi<gN>2<0>3<I>

Calculated: C 41.28% H 5.06% N 7.40% I 33.55%

Found : C 41.52% H 5.12% N 7.14% I 32.97%

Example 11

4.14 g of 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido [1,2-a]azepine was boiled with 1.3 ml of dimethyl sulfate in 50 ml of methanol for 1 hour , and the reaction mixture was evaporated to half the volume. The mixture was allowed to stand for 24 hours at a temperature below 0° C and allowed to crystallize. The precipitated crystals were filtered. 5.5 g of 3-carbaomyl-1-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepinium methylsulfate melting at 191 - 193 were obtained °C.

Analysis: c12<H>i<gN>3°6S

Calculated: C 43.23% H 5.74% N 12.60% S 9.62%

Found : C 43.05% H 5.61% N 12.58% S 9.53%

Example 12

11.2 g of 7-amino-3,4,5,6-tetrahydro-2H-azepine and 19.2 g of ethyl-2-formyl-phenyl-acetate were boiled in 100 ml of absolute alcohol for 5 hours, and the reaction mixture was evaporated . The residue was treated with a mixture of acetone and petroleum ether. The solid product obtained was filtered. 22 g (91%) of a mixture of 3-phenyl-2-oxo-2,6,7,8,-9,10-hexahydro-pyrimido[1,2-a]azepine and 3-phenyl- 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine. Melting point 126 - 130° C (melted slowly).

Analysis: C, r-H, ,No0

J 15 16 2.

Calculated: C 74.97% H 6.71% N 11.66%

Found : C 74.21% H 6.58% N 11.44%

Example 13

1 g of the product prepared in example 12, which contains a mixture of 3-phenyl-2-oxo-2,6,7,8,9,10-hexa-hydro-pyrimido [1,2-a]azepine and 3 -phenyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido [1,2-a]azepine, was placed on a silica gel column (10 g). The diameter of the column was 1 cm and the grain size of the silica gel was 0.063 - 0.125 mm. The column was eluted with ethyl acetate. After evaporation of the ethyl acetate eluate, pure 3-phenyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-[1,2-a]azepine was obtained which melts at 156 - 158° C .

Analysis: C^H^N-jO

Calculated: C 74.97% H 6.71% N 11.66%

Found : C 74.93% H 6.70% N 11.58%

After removal of 3-phenyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine, the column was further eluted with methanol, and after concentration of the methanolic eluate, obtained 3-phenyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido [1,2-a]azepine melting at 215 - 216°C.

Analysis: c15<H>i6<N>2°

Calculated: C 74.97% H 6.71% N 11.66%

Found : C 74.85% H 6.68% N 11.42%

Example 14

5.6 g of 7-amino-3,4,5,6-tetrahydro-2H-azepine and 7.5 g of ethyl-2-ethyl-acetoacetate were boiled in 50 ml of ethanol for 3 hours. The ethanol was distilled at reduced pressure. The remaining oil was dissolved in 20 ml of 10% hydrochloric acid solution and shaken twice with 10 ml of ethyl acetate. The aqueous phase was neutralized with sodium bicarbonate and shaken with 3 x 10 ml of chloroform. The combined chloroform phase was dried over calcined sodium sulfate and concentrated. The remaining colorless oil was fractionated under reduced pressure. 6.3 g (61%) of 3-ethyl-2-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-fl , 2-a]azepine was obtained which distils at 156 - 160° C at 2 mmHg.

Analysis: c12<H>18<N>2°

Calculated: C 69.87% H 8.79% N 13.58%

Found : C 69.98% H 8.85% N 13.22%

Pharmacological tests:

The anti-anginal activity of the compounds was determined by the inhibition of acute coronary insufficiency produced by intravenous administration of Vasopressin (Arch. Int. Pharmacodyn. 160, 147, 1966).

The investigated compounds were administered intravenously dissolved in water.

Acute toxicity of 2-oxo-2,6, lf8,9,10-hexahydro-pyrimido [1 , 2-a] azepin-4 -one in CFY rats is 600 2000 mg/kg by intravenous administration and 1000 - 3000 mg /kg by oral administration.

Acute toxicity of 4-oxo-4, ,6,7,8,9,10-hexahydro-pyrimido [1,2-a]azepin-2-one in CFY rats is 400 - 900 mg/kg by intravenous administration and 900 r 25.00 mg/kg by oral administration..

Claims (1)

Analogy process for the preparation of therapeutically active compounds of general formula of a mixture of these and pharmaceutically suitable acid addition salts and quaternary salts, in which R denotes hydrogen or lower alkyl, R<1> denotes lower alkyl, phenyl, carboxyl, lower alkoxycarbonyl, nitrile, carbamoyl_, carbohydrazido, R<2> denotes hydrogen, or R<2> is lower alkyl only when R- is lower alkyl, provided that when R 2 in formula I denotes hydrogen, R<1> in formula I cannot denote nitrile, alkoxycarbonyl or propyl, characterized in that a 7-amino-3,4,5,6-tetrahydro-2H-azepine derivative of general formula in which R is as indicated above, is reacted with the acrylic acid derivative of general formula 2 3 wherein R is as indicated above, R denotes lower alkyl, phenyl, lower alkoxycarbonyl, nitrile, R denotes hydrogen or lower alkyl, R^ denotes lower alkyl, and if desired, that the obtained mixture of 4-oxo-pyrimido[1,2-a]azepine of general formula I and 2-oxo-pyrimido[1,2-a]azepine of general formula II is separated from each other, and if desired that an obtained 2 1 compound in which R and R are as indicated above and R be denotes alkoxycarbonyl, a) transferred by saponification in a carboxylic acid in which R and 2 1 R are as indicated above and R denotes carboxy, or b) transferred by reaction with ammonia to an acid amide - 2 1 in which R and R are as indicated above and R denotes carbamoyl, or c) is transferred by reaction with hydrazine to a compound 2 1 in which R and R are as indicated above, and R denotes carbohydrazido, and, if desired, that an obtained compound of general formula I or II is transferred to a pharmaceutically suitable acid addition salt or quaternary salt.